Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT2A receptors and D2-type receptors. Predominant 5HT2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D2 antagonism is required the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D3 and in particular D4 receptors has been proposed. In vitro, all compounds, except the 'typical' antipsychotics haloperidol and fluspirilene, showed higher affinity for 5HT2A than for D2 receptors. Subnanomolar affinity for human 5HT2A receptors was observed for ORG-5222, sertindole, risperidone, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperidol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D2 receptors. Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D2 affinity in vitro. Clozapine, but even more so pipamperone, displayed higher affinity for D4 than for D2 receptors. For most other compounds, D4 affinity was only slightly lower than their D2 affinity. Seroquel was totally devoid of D4 affinity. None of the compounds had nanomolar affinity for D1 receptors; their affinity for D3 receptors was usually slightly lower than for D2 receptors. In vivo, ORG-5222, risperidone, pipamperone, 9-OH-risperidone, sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT2A than D2 receptors. Risperidone and ORG-5222 had 5HT2A versus D2 potency ratio of about 20. Highest potency for 5HT2A receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT2A receptors. ORG-5222, haloperidol, fluspirilene and olanzapine showed the highest potency for occupying D2 receptors. No regional selectivity for D2 receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D2 receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic alpha 1 receptors, except fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more alpha 1 than D2 receptors. Clozapine showed predominant occupancy of H1 receptors and occupied cholinergic receptors with equivalent potency to D2 receptors. A stronger predominance of 5HT2A versus D2 receptor occupancy combined with a more gradual occupancy of D2 receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT2A receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D2 receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT2A and D2 occupancy and the avoidance of D2 receptor overblockade are believed to reduce the risk for extrapyra
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PMID:Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. 893 1

A major role of the serotonergic system has been hypothesized in the pathogenesis of schizophrenia, mostly based on the evidence of action of new and atypical neuroleptics such as Risperidone or Clozapine. We evaluated the genotypes and alleles of the 5HT2a receptor gene in 67 nuclear families following the Haplotype Relative Risk (HRR) strategy and in a second sample of 100 schizophrenics and 103 controls. The 5HT2a receptor gene polymorphism, following PCR amplification and subsequent Hpa II digestion, reveals a two-alleles system in the coding region of the gene. We did not find statistically significant differences between patients and controls for genotypes, nor for alleles, both in the HRR and in the case-control groups. These results do not confirm the positive association obtained by Inayama et al.: [Neuropsychopharmacology 1(35): 145-219, 1994] and by Williams et al. [Lancet, 397:1294-1296, 1996] in our population.
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PMID:No association between schizophrenia and the serotonin receptor 5HTR2a in an Italian population. 903 1

New, so-called atypical antipsychotic medications will no doubt supplant the traditional, or "typical," antipsychotic medications, just as the new generation of antidepressant agents has replaced the older tricyclic drugs. At issue with most of the new drugs is not acute efficacy, but long-term tolerability. Side effects must be minimized to enhance compliance and prevent relapse. It appears that many of the new antipsychotic drugs have fewer or less troublesome side effects than the older agents. In addition, the "atypical" antipsychotic agents hold promise for treating refractory schizophrenia. At present, only clozapine, with its risks for agranulocytosis and seizures, is clearly established as a treatment for refractory illness. Risperidone may be an alternative for treatment-resistant schizophrenia, but this has not yet been clearly proved. Olanzapine has recently been introduced. Sertindole should be available soon, and quetiapine and ziprasidone should quickly follow. Safety, efficacy, and cost will guide their use. None of these newer agents have been compared head-to-head with clozapine. More research is needed to place these new drugs into clinical perspective.
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PMID:New antipsychotic medications: what advantages do they offer? 904 36

Risperidone was effective in successfully treating a patient's negative symptoms of schizophrenia as well as reducing adverse effects from typical antipsychotic drugs. Auditory hallucinations reemerged after 8 months, however, and again after 24 months of risperidone therapy. Reemergence of psychotic symptoms after initial response might be explained by inadequate dosage, by the natural course of the patient's schizophrenia independent of drug therapy, or by the possibility that, for this patient, risperidone was less effective than chlorpromazine for the positive symptom of auditory hallucinations.
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PMID:Reemergence of positive symptoms after initial response to risperidone. 908 34

In radioligand binding studies, BIMG 80, a new putative antipsychotic, displayed good affinity at certain serotonin (5-HT1A, 5-HT2A, 5-HT6), dopamine (D1, D2L, D4), and noradrenergic (alpha1) receptors. The effect of acute subcutaneous BIMG 80, clozapine, haloperidol, risperidone, amperozide, olanzapine, and Seroquel was then investigated on dopamine release in medial prefrontal cortex, nucleus accumbens, and striatum in freely moving rats using the microdialysis technique. Four different neurochemical profiles resulted from the studies: (a) Systemic administration of BIMG 80, clozapine, and amperozide produced greater percent increases in dopamine efflux in medial prefrontal cortex than in the striatum or the nucleus accumbens. (b) Haloperidol induced a similar increase in dopamine concentrations in the striatum and nucleus accumbens with no effect in the medial prefrontal cortex. (c) Risperidone and olanzapine stimulated dopamine release to a similar extent in all brain regions investigated. (d) Seroquel failed to change significantly dopamine output both in the medial prefrontal cortex and in the striatum. Because an increase in dopamine release in the medial prefrontal cortex may be predictive of effectiveness in treating negative symptoms and in the striatum may be predictive of induction of extrapyramidal side effects, BIMG 80 appears to be a potential antipsychotic compound active on negative symptoms of schizophrenia with a low incidence of extrapyramidal side effects.
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PMID:BIMG 80, a novel potential antipsychotic drug: evidence for multireceptor actions and preferential release of dopamine in prefrontal cortex. 920 9

The efficacy and safety of risperidone have previously been demonstrated in controlled clinical trials in hospitalized chronic schizophrenia patients who met strict research criteria. The present study was designed to evaluate the efficacy and safety of risperidone in a heterogeneous patient population. Patients were enrolled in the study if they had a diagnosis of schizophrenia (DSM-III-R) with or without acute exacerbation. Of the 945 patients from 158 psychiatric centers who entered this phase IV study, 558 completed the 10-week trial. During week 1, the dose of risperidone was titrated to 6 mg/day, maintained there for 1 week, and then adjusted over a 4-week period as clinically necessary; the dose was then fixed for the final 4-week period. The mean dose of risperidone at endpoint was 5.9 mg/day. Patients were evaluated at baseline and at weeks 2, 6, and 10, using Clinical Global Impression scale, Psychotic Symptoms Assessment scale, and Global Assessment of Functioning scale. Significant improvement in mean scores was found on each of these measures at endpoint. Comparable results were obtained at week 10 in treatment-resistant and non-treatment-resistant patients. Risperidone was generally well tolerated and the severity of extrapyramidal symptoms was significantly reduced at endpoint.
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PMID:A clinical evaluation of risperidone in the treatment of schizophrenia: a 10-week, open-label, multicenter trial. ARCS Study Group. Assessment of Risperdal in a Clinical Setting. 920 34

A series of 14 children and adolescents (ages 9-17 years, 10 males) were treated with risperidone for pervasive developmental disorder. The rationale for using an atypical neuroleptic agent is based on its ability to target both positive and negative symptoms of schizophrenia. It was postulated that symptoms similar to the positive and negative symptoms of schizophrenia may be observed in the pervasive developmental disorders and might respond favorably to risperidone. Twelve of the 14 youths had been treated previously with several psychotropic drugs, often concurrently. Risperidone was initiated at a starting dose of 0.25 mg twice daily and increased in 0.25 mg/day increments every 5-7 days. Optimal dosages ranged from 0.75 to 1.5 mg daily in divided doses. Thirteen of the 14 youths appeared to benefit from risperidone. Improvement in functionality on the Children's Global Assessment Scale was demonstrated in 13 of 14 cases. Disruptive behaviors, when present, markedly decreased on risperidone. Ten patients showed a marked reduction in agitation and anxiety. Social awareness improved markedly in 10 patients, moderately in 3, and only slightly in 1. All but 1 patient demonstrated a lessening in obsessional behaviors. Effects on attention were uniformly positive. Side effects were minimal at the dosages used in this study; 5 patients had initial sedation. Neither extrapyramidal side effects nor agitation was observed in any case. Ten of 14 youths could be managed with risperidone monotherapy. During the follow-up period (mean 7 months), none of the patients experienced a major relapse while taking risperidone. Positive and negative symptoms, as typically characterized in schizophrenia, were both found to improve equally well with risperidone treatment. Based on these findings, a prospective clinical trial with a randomized controlled design is warranted.
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PMID:Use of risperidone in pervasive developmental disorders: a case series. 923 11

Risperidone is a newly available atypical antipsychotic agent that has been reported to be associated with fewer extrapyramidal side effects (EPS) than conventional neuroleptics in adults with schizophrenia. This study assessed the safety and efficacy of risperidone in 16 children and adolescents (aged 9-20 years, mean 14.9 years) who were clinically diagnosed with psychotic disorders: 13 patients met DSM-III-R criteria for schizophrenia, 2 met criteria for schizoaffective disorder, and 1 had schizophreniform disorder. Eleven of the 16 patients had previous unsuccessful neuroleptic trials. Patient charts were reviewed by the patients' child and adolescent psychiatrist for diagnoses, clinical changes, and adverse events. Clinical response was assessed retrospectively using the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression (CGI) scale. With the risperidone dose titrated gradually, an optimal clinical response was found at a mean daily risperidone dose of 5.93 mg (range 2-10 mg). All but one of the 16 patients had an adequate clinical response to risperidone therapy. Statistically significant improvements were found in the CGI (p < 0.0001), the BPRS Total Score (p < 0.0001), and the BPRS Negative Symptom Score (p < 0.001). In general, only mild drug-induced side effects were experienced, with 5 patients developing mild sedation and 3 developing EPS. Risperidone appeared to be safe and effective in ameliorating symptoms of schizophrenia in this age group. It is speculated that the gradual titration of risperidone was crucial in achieving a relatively low rate of EPS.
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PMID:Risperidone in the treatment of children and adolescents with schizophrenia: a retrospective study. 923 18

Risperidone is an antipsychotic drug used for the treatment of schizophrenia. It was expected that this atypical neuroleptic agent would not cause dystonia or neuroleptic malignant syndrome (NMS) owing to its unique mechanism of action with attenuated anti-dopaminergic activity and more potent antiserotoninergic activity. We report the case of a geriatric patient in whom signs and symptoms consistent with NMS developed after 3 weeks of risperidone therapy. The patient presented with fever, mental status changes, tremor, and rigidity. His laboratory findings were significant for increased serum creatine phosphokinase, hypernatremia, and metabolic acidosis. There have been few reported cases of risperidone-induced NMS. Health care providers should be aware of the risk of risperidone-induced NMS.
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PMID:Risperidone-induced neuroleptic malignant syndrome. 936 May 86

Since schizophrenia is not a rare occurrence and is often chronic, the general practitioner and internist providing primary care should also be informed on new developments in treatment with neuroleptics. A major new form of treatment is provided by the so-called atypical neuroleptics which, however, in terms of their receptor specificity are not a uniform group, and have only a few properties in common. A prototype of this group is clozapine (Leponex), which has a good antipsychotic effect and virtually no action on the extrapyramidal motor system (EPS). Whether clozapine is also capable of improving the primary negative symptoms of schizophrenia (e.g. flattering of affect, reduction of drive, cognitive disorders, etc.) has not yet been ascertained. On account of the rare but possibly fatal agranulocytosis it may induce, it may be prescribed only when certain safety precautions are taken. Risperidone (Risperdal) has similar efficacy against the classical positive symptoms, with no action on the EPS (up to a medium dosage), and has no hematological effects. Other atypical neuroleptics have recently become available: quetiapine, olanzapine and sertindole. They have at least some of the advantages of clozapine but a very low risk of producing hematological effects. However, before they are widely used in the doctor's practice, further clinical experience is needed.
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PMID:[Atypical neuroleptics--the future of schizophrenia treatment?]. 952 41


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